Olaparib maintenance for ovarian cancer most effective in women with BRCA mutations

Women with platinum-sensitive recurrent serous ovarian cancer who harbored BRCA mutations are more likely than BRCA wild-type patients to benefit from maintenance monotherapy with olaparib, results of a phase 2 study suggest.

“To our knowledge, our study is the first phase 2 trial in ovarian cancer to show that patients with BRCA1 or BRCA2 mutations respond preferentially to a PARP inhibitor,” Jonathan Ledermann, MD, of UCL Cancer Institute at University College London, and colleagues wrote.

Ledermann and colleagues conducted a randomized, double blind study that included 265 women with platinum-sensitive recurrent serous ovarian cancer. All patients received at least two platinum-based regimens and demonstrated a complete or partial response to their most recent platinum-based regimen.

Researchers randomly assigned 136 patients to twice-daily 400 mg olaparib (AZD2281, AstraZeneca). The other 129 patients received placebo.

PFS served as the primary endpoint. Secondary endpoints included OS, best overall response, health-related quality of life, safety and tolerability.

Seventy-four patients (56%) in the olaparib group and 62 patients (50%) in the placebo group had known deleterious or suspected deleterious BRCA mutations.

Olaparib significantly extended median PFS among patients with BRCA mutations (11.2 months vs. 4.3 months; HR=0.18; 0.10-0.31) and BRCA wild-type patients (7.4 months vs. 5.5 months; HR=0.54; 95% CI, 0.34-0.85).

Results of an interim analysis showed median OS did not differ significantly between patients assigned olaparib and those assigned placebo (29.8 months vs. 27.8 months; HR=0.88; 95% CI, 0.64-1.21). Researchers reported longer median OS with olaparib in the BRCA-positive cohort (34.9 months vs. 31.9 months; HR=0.73; 95% CI, 0.45-1.17) and the BRCA wild-type cohort (24.5 months vs. 26.2 months; HR=0.99; 95% CI, 0.63-1.55), but the differences were not statistically significant.

However, they determined olaparib was associated with longer median time to second subsequent therapy or death than placebo among BRCA-positive patients (23.8 months vs. 15.2 months; HR=0.44; 95% CI, 0.29-0.67) and BRCA wild-type patients (17.1 months vs. 14.7 months; HR=0.64; 95% CI, 0.42-0.96).

William D. Foulkes

Researchers reported serious adverse events in 18% of patients assigned olaparib and 9% of patients assigned placebo. Incidence of grade ≥3 fatigue (7% vs. 3%) and anemia (5% vs. <1%) was higher in the olaparib group. Tolerability of olaparib among patients with BRCA mutations was comparable to that observed in the overall study population.

The results show olaparib led to greater clinical benefit in patients with BRCA mutations and support the hypothesis that patients with tumors that harbor a homologous recombination deficiency, including BRCA mutations, respond preferentially to PARP inhibitors, Ledermann and colleagues concluded.

“Testing of all women with high-grade serous carcinoma of the gynecological tract should be a clinical imperative — not only, as in previous practice, to benefit these women’s relatives, but also to extend the lives of the patients themselves,” William D. Foulkes, MB, PhD, a professor in the departments of medicine, human genetics and oncology and director of the Program in Cancer Genetics at McGill University in Montreal, wrote in an accompanying editorial. “This study gives added momentum to made-to-measure medicine.”

For more information:

Foulkes WD. Lancet Oncol. 2014;doi:10.1016/S1470-2045(14)70228-1.
Ledermann J. Lancet Oncol. 2014;doi:10.1016/S1470-2045(14)70246-3.

Disclosure: The researchers report grant support from AstraZeneca; advisory board roles with Amgen, AstraZeneca, Boehringer Ingelheim, Clovis, Oxigene and Roche; consultant roles with AstraZeneca; and employment relationships with and stock ownership in AstraZeneca.